Abstract
Background Campylobacter jejuni is a leading cause of foodborne bacterial enterocolitis worldwide. Investigation of immunopathology is hampered by a lack of suitable vertebrate models. We have recently shown that gnotobiotic mice as well as conventional IL-10−/− animals are susceptible to C. jejuni infection and develop intestinal immune responses. However, clinical symptoms of C. jejuni infection were rather subtle and did not reflect acute bloody diarrhea seen in human campylobacteriosis.Methodology/Principal FindingsIn order to overcome these limitations we generated gnotobiotic IL-10−/− mice by quintuple antibiotic treatment starting right after weaning. The early treatment was essential to prevent these animals from chronic colitis. Following oral infection C. jejuni colonized the gastrointestinal tract at high levels and induced acute enterocolitis within 7 days as indicated by bloody diarrhea and pronounced histopathological changes of the colonic mucosa. Immunopathology was further characterized by increased numbers of apoptotic cells, regulatory T-cells, T- and B-lymphocytes as well as elevated TNF-α, IFN-γ, and MCP-1 concentrations in the inflamed colon. The induction of enterocolitis was specific for C. jejuni given that control animals infected with a commensal E. coli strain did not display any signs of disease. Most strikingly, intestinal immunopathology was ameliorated in mice lacking Toll-like-receptors-2 or -4 indicating that C. jejuni lipoproteins and lipooligosaccharide are essential for induction and progression of immunopathology.Conclusion/SignificanceGnotobiotic IL-10−/− mice develop acute enterocolitis following C. jejuni infection mimicking severe episodes of human campylobacteriosis and are thus well suited to further dissect mechanisms underlying Campylobacter infections in vivo.
Highlights
Campylobacter (C.) jejuni is a leading cause of bacterial-induced enteritis worldwide
We have recently shown that 5 to 6 months old IL-102/2 mice harboring a conventional intestinal microbiota and suffering from chronic colitis could be stably infected with C. jejuni at intermediate levels in approximately 70% of cases, but symptoms were rather subtle and, ’’classical’’ clinical signs of severe human camplyobacteriosis such as bloody diarrhea were missing
Using gnotobiotic wildtype mice in which the microbiota had been completely eradicated by antibiotic treatment or gnotobiotic mice reconstituted with a human microbiota oral C. jejuni infection resulted in stable gastrointestinal colonization and pro-inflammatory immune responses in the colon [22,23]
Summary
Campylobacter (C.) jejuni is a leading cause of bacterial-induced enteritis worldwide. In a very recent study we could clearly demonstrate that artificially elevating the intestinal E. coli burden by feeding live bacteria to adult mice harboring a conventional gut microbiota (and rendering them resistant to C. jejuni infection) abolished colonization resistance and C. jejuni infection induced pro-inflammatory immune responses within the infected gut [24]. Severe clinical symptoms of acute enterocolitis such as bloody diarrhea in human campylobacteriosis were missing in so far generated animal models. Very recently we demonstrated that infection of 3-weeks-old infant mice right after weaning, but not adult 3-months-old animals harboring an age-dependent conventional intestinal microbiota developed acute enterocolitis within 6 days p.i. as indicated by bloody diarrhea, colonic shortening and increased apoptotic cell numbers in the colon mucosa. Clinical symptoms of C. jejuni infection were rather subtle and did not reflect acute bloody diarrhea seen in human campylobacteriosis
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